A Mechanistic Probe into 1,2-cis Glycoside Formation Catalyzed by Phenanthroline and Further Expansion of Scope

Article abstract of DOI:10.1002/adsc.202100639

Phenanthroline, a rigid and planar compound with two fused pyridine rings, has been used as a powerful ligand for metals and a binding agent for DNA/RNA. We discovered that phenanthroline could be used as a nucleophilic catalyst to efficiently access high

Full text of DOI:10.1002/adsc.202100639

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100639
Very Important Publication
A Mechanistic Probe into 1,2-cis Glycoside Formation Catalyzed
by Phenanthroline and Further Expansion of Scope
Jiayi Lia and Hien M. Nguyena,*
a
Department of Chemistry, Wayne State University, Detroit, Michigan, 48202, United States
E-mail: hmnguyen@wayne.edu
Manuscript received: May 25, 2021; Revised manuscript received: June 22, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100639
Abstract: Phenanthroline, a rigid and planar compound with two fused pyridine rings, has been used as a
powerful ligand for metals and a binding agent for DNA/RNA. We discovered that phenanthroline could be
used as a nucleophilic catalyst to efficiently access high yielding and diastereoselective α-1,2-cis glycosides
through the coupling of hydroxyl acceptors with α-glycosyl bromide donors. We have conducted an extensive
investigation into the reaction mechanism, wherein the two glycosyl phenanthrolinium ion intermediates, a 4C1
chair-liked β-conformer and a B2,5 boat-like α-conformer, have been detected in a ratio of 2:1 (β:α) using
variable temperature NMR experiments. Furthermore, NMR studies illustrate that a hydrogen bonding is
formed between the second nitrogen atom of phenanthroline and the C1-anomeric hydrogen of sugar moiety to
stabilize the phenanthrolinium ion intermediates. To obtain high α-1,2-cis stereoselectivity, a Curtin-Hammett
4
scenario was proposed wherein interconversion of the C1 chair-like β-conformer and B2,5 boat-like α-
conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the α-face of the more
4
reactive C1 β-phenanthrolinium intermediate to give an α-anomeric product. The utility of the phenanthroline
catalysis is expanded to sterically hindered hydroxyl nucleophiles and chemoselective coupling of an alkyl
hydroxyl group in the presence of a free C1-hemiacetal. In addition, the phenanthroline-based catalyst has a
pronounced effect on site-selective couplings of triol motifs and orthogonally activates the anomeric bromide
leaving group over the anomeric fluoride and sulfide counterparts.
Keywords: Phenanthroline, NMR Study; Kinetics; 1,2-cis Glycosides; Stereo- and Site-Selective; Orthogonal
Activation
Introduction
approaches to the formation of α- or β-selective CÀ O
bonds at the anomeric center.
The field of glycoscience has burgeoned in the last
Despite recent breakthroughs,[2] glycan synthesis
decades, leading to the identification of glycans that remains a challenging endeavor because of the stereo-
play critical roles in a wide range of biological selective installation of glycosidic CÀ O linkages. In
processes.[1] This rapid growth of knowledge about the particular, the identification of approaches to the
function of glycans has attracted increasing attention coupling of hydroxyl acceptor (nucleophile) with sugar
from biological, pharmacological, and medicinal re- donor (electrophile) to form 1,2-cis glycosidic linkage
searchers. Meeting their research demands requires in high yield and diastereoselectivity remains a major
access to significant quantities of well-defined natural goal. Glycosylation strategies often rely on neighbor-
and unnatural glycans. Further, access to biologically ing group participation, steric and electronic properties,
relevant oligosaccharides and glycoconjugates enables and directing effects to influence 1,2-cis selectivity.[3]
the identification protein binding epitopes and provides As a result, they remain substrate-dependent. In
standards for the development of analytical method- addition, subtle changes to carbohydrate structure or
ologies. This has prompted resurgence in synthetic protecting groups have profound impacts on the
interest, with a particular focus on new and robust glycosylation reactivity and selectivity.
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The use of catalysts, which are consisted of of phananthroline as a nucleophilic catalyst in organic
enzymes, transition-metal complexes, or small organic reactions or stereoselective glycosylations until our
molecules, has emerged as a promising strategy to recent discovery.[8] Our initial proposed mechanism
address the challenges associated with carbohydrate evolved from a basic principle: two pyridine nitrogen
synthesis.[4] Particularly, nucleophilic catalysts play a atoms are positioned to act cooperatively (Scheme 2).
central role in expanding chemical space of small The first nitrogen atom acts as a catalytic nucleophile
organic molecule catalysis and are capable of catalyz- to displace the C1-anomeric bromide leaving group of
ing a variety of organic transformations.[5,6] A wide a glycosyl donor, via an SN2-like pathway, to generate
range of Lewis bases, tertiary phosphines/amines, an equatorial (β) phenanthrolinium ion intermediate
pyridines, and imidazoles, have been showed to act as preferentially to avoid the steric interactions associated
effective, nucleophilic catalysts.[5] For instance, glyco- with positioning that group in the axial (α) orientation.
sylation reaction promoted by pyridine has been The second nitrogen atom could interact with carbohy-
reported.[7] However, the pyridine-promoted reaction drate moiety to further stabilize the phenanthrolinium
proceeds with marginal diastereoselectivity for α-1,2- ion intermediate. Subsequent SN2-like substitution by a
cis glycoside due to the competing formation of β-1,2- hydroxyl nucleophile leads to the formation of α-1,2-
trans glycoside.
cis glycosides.
We recently discovered that phenanthroline effec-
Detection of Glycosyl Phenanthrolinium Ion
tively catalyzed the glycosylation of a variety of Intermediates. For the phenanthroline-catalyzed gly-
alcohol nucleophiles with α-glycosyl bromides to cosylation to yield α-1,2-cis product, the catalyst must
provide α-1,2-cis glycosides with the net retention of associate with either or both substrates in the reaction.
the anomeric configuration (Scheme 1).[8] This phenan- In our proposed mechanism (Scheme 2), phenanthro-
throline catalysis system provides a general platform line displaces the bromide leaving group to form a
for predictable and stereoselective formation of 1,2-cis glycosyl phenanthrolinium ion intermediate. Unlike
glycosidic linkages under mild and operationally sugars, phenanthroline is a rigid and planar organic
simple conditions. As a result, a proper mechanistic compound with a C2 symmetry. However, if phenan-
understanding of phenanthroline-catalyzed glycosyla- throline is coupled with a sugar molecule, the
tion is critical for the development of robust α-1,2-cis symmetry will be destroyed. As a result, our first
glycoside procedure. Herein, we report the use of objective was to perform 1H NMR study to observe the
deuterated glucosyl bromide as a glycosyl donor and symmetry on phenanthroline (Figure 1). To obtain a
1
examined the stereochemical outcome of glycosyla- clear view on the aromatic region in H NMR, 2,3,4,6-
tions with piperidine substituted phenanthroline cata- tetra-benzyl-d7-glucopyranosyl bromide 1* was used
lyst. We unveiled the mask of the glycosyl phenan- as an electrophile, wherein the chemical shift of
throlinium
ion
intermediates
using
variable anomeric proton (H1) resonance appeared at δH =
temperature NMR (1H, COSY, and ROESY) experi- 6.55 ppm in CD2Cl2 (Figure 1a). Piperidine substituted
ments. Kinetic studies showed that the rate of phenanthroline C2 was chosen for our NMR study
glycosylation is dependent on the concentration of the because it is the most effective catalyst[10] compared to
phenanthroline catalyst, glycosyl donor, and acceptor. other catalysts,[8] implying formation of the reactive
A detailed understanding of phenanthroline-catalyzed glycosyl intermediates is more favorable. In addition,
glycosylation mechanism has led to a broader scope.
This phenanthroline catalyst system not only fulfills
high α-1,2-cis diastereoselectivity, but also enables
high chemo- and site-selectivity.
Results and Discussion
Phenanthroline has been utilized extensively as a
powerful ligand for metals and a binding agent for
DNA/RNA.[9] However, there was no report on the use
Scheme 2. Proposed mechanism of the phenanthroline-cata-
Scheme 1. Phenanthroline-catalyzed α-1,2-cis glycosylations
lyzed α-1,2-cis glycosylations
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Figure 1. Detection of phenanthrolinium intermediate by H NMR: (a) Deuterated tetra-benzyl glucosyl bromide 1* in CD2Cl2; (b)
1* and 10 mol% C2 at 0 min; (c) 1* and C2 at 30 min, new signals emerging around phenanthroline aromatic region; (d) 1*, 2, C2
at 30 min, disaccharide 3* emerging; and (e) 1*, 2, C2 at 300 min, more disaccharide 3* formed in the reaction. See supporting
information for full spectra.
the chemical shift of the piperidyl substituents would mass spectrometry and returned m/z ratio of 897.6393,
not appear in the aromatic region. To avoid any confirming the presence of the intermediate Int*
possible side reaction with by-product of isobutyl (Figure 1) which resembled a phenanthrolinium ion.
oxide (IBO),[10] di-tert-butylmethylpyridine (DTBMP) Hydroxyl nucleophile 2 was subsequently added to the
was chosen as the acid scavenger in the later NMR reaction mixture along with DTBMP and mesitylene
experiment (Figure 1).
(internal standard). After 30 min, new signals still
Upon addition of 10 mol% of C2 to the deuterated surrounded the aromatic region (Figure 1d) along with
glycosyl bromide 1*, three new signals appeared at the appearance of the disaccharide product whose
δH =8.88 ppm (Ha, d, J=5.0 Hz) and δH =7.07 ppm anomeric proton appeared at δH =5.03 ppm (d, J=
(Hb, d, J=5.1 Hz) and the singlet at δH =7.98 ppm 3.6 Hz, Figure 1d). At 5 h, more product was formed
(Hc) represented the symmetry of C2 catalyst (Fig- and the new peaks remained at the aromatic region
ure 1b). Within 30 min, new signals emerged around (Figure 1e). The reaction mixture was allowed to stir
°
the phenanthroline region (Figure 1c). These new overnight at 25 C. The product 3* was isolated in
signals were not detected in the mixture of nucleophile comparable yield (80%) and selectivity (α:β=10:1) to
2 and C2 (Figure S1). An aliquot of the reaction that of disaccharide 3 (vide infra, Table 1, entry 4).
mixture was subjected to electrospray ionization (ESI) Several key observations were obtained from this
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NMR experiment: (1) the new signals appeared to be were calculated at the B3LYP/6-31+G(d,p) level[11]
doublets, indicating the newly-formed phenanthroline with the SMD implicit solvent model[12] and the
species did not maintain their symmetry; (2) the GD3BJ empirical dispersion correction[13]. All calcu-
number of signals suggests that there are two possible lations were carried out with Gaussian 09.[14] In our
phenanthroline species (Int1 and Int2) present in the DFT calculations, tetramethyl glucosyl bromide was
solution (Figure 2); (3) the population of unbound used as a model electrophile to reduce computational
phenanthroline C2 and the two phenanthroline species cost (Figure 2). The DFT calculation results are
(Int1 and Int2) shifted from 76:14:10 (C2: Int1: Int2) consistent with our NMR data.
to 81:12:7 upon addition of alcohol 2, suggesting the
Employing 2D COSY NMR, the newly formed
equilibrium of the catalyst states had shifted toward protons in the phenanthroline aromatic region resided
regeneration of C2, likely through formation of the at δH =8.68 ppm (d, J=8.1 Hz) and δH =8.36 ppm (d,
coupling product; and (4) the integration of the signals J=3.6 Hz) were identified to be the C1 protons of the
suggested that an extra hydrogen atom appeared on the anomeric mixture of Int1 (β) and Int2 (α), in a ratio of
phenanthroline aromatic region for each newly-formed 2:1 (β:α) (Figure 2). Suggested by DFT calculations
species, which was subsequently identified as a C1- (Figure 2), while Ha proton on the phenanthroline is
proton of the sugar unit (vide infra, Figure 2).
spatially closed to the C2 proton for the β-isomer Int1
To further identify the presence of the two newly- (2.646 Å), the Ha proton for the α-isomer Int2 is closed
formed species upon mixing deuterated glycosyl to the C5 proton (2.700 Å) on the sugar ring. These
bromide 1* with C2, a 1:1 stoichiometry ratio of 1* spatial interactions were also observed through 2D
and C2 catalyst was employed. As the concentration of ROESY NMR, which consolidate the anomeric config-
C2 increased, the equilibrium shifted toward the two urations for the two detected intermediates. Similar to
new intermediates, wherein the population of unbound the glycosyl pyridinium ion,[7,15] the major phenanthro-
C2 catalyst, Int1 and Int2 became 55%, 30%, and linium ion intermediate is a β-configured isomer (Int1)
1
4
15%, respectively (see SI for H NMR spectrum). and exists in the C1 chair conformation while the
Variable temperature 1H, 1H-1H 2D COSY and ROESY minor α-isomer (Int2) exists in the B2,5 boat conforma-
°
NMR spectra at 0 C were subsequently obtained. tion to avoid stereo- and electronic effect from the
Density functional theory (DFT) calculations were ring.
employed to assist the deconvolution of these inter-
Hydrogen Bonding in the Phenanthrolinium Ion
mediates. The geometries of possible intermediates’ Intermediates. Several NMR evidences were found
structures were optimized and vibrational frequencies below to support hydrogen bonding (H-bonding)
interaction between the second nitrogen of phenanthro-
line and the C1 anomeric proton. In general, for H-
bonding involving an electronegative acceptor such as
oxygen or nitrogen, the donor nucleus experiences a
deshielding effect.[16] Conversely, if the C1 anomeric
proton is hydrogen bonding to the second nitrogen of
phenanthroline, the chemical shift should appear more
downfield in the 1H NMR. It has been reported that the
anomeric proton of β-glucosyl pyridinium bromide
resonances at δH =6.10 ppm in D2O.[17] In addition,
Gin and coworker established anomeric mixture of
glycosyl pyridinium species, wherein the anomeric
protons resonance at δH =6.63 and 6.49 ppm in CD2Cl2
[18]
1
°
at À 60 C. However, the H NMR spectra of a 1:1
mixture of glycosyl bromide 1* and C2 taken at
°
À 60 C (see Figure S3) showed the anomeric protons
of the intermediates, Int1 (β) and Int2 (α), resonance at
δH =8.44 and 8.18 ppm, respectively (Figure 2). The
downfield shift of the anomeric protons of glycosyl
phenanthrolinium ion intermediates compare to that of
the reported glycosyl pyridinium species is likely due
to an intramolecular hydrogen bonding between the
anomeric proton and second nitrogen on phenanthro-
line.
Figure 2. Conformation of the glycosyl phenanthrolinium ion
1
intermediates: H-1H 2D COSY (red) and ROESY (blue) NMR
A more direct hydrogen bonding observation is
through hydrogen bond scalar coupling.16 The scalar
interaction arises from electron cloud between nuclei,
evidence (see Figure S2 for correlations) as well as DFT
calculation structures.
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such as covalent bonds. Upon formation of H-bonding,
Proposed Mechanism. Based on the NMR study
the redistribution of electron density of the nuclei and DFT calculations,[10] a proposed mechanism for the
associate with H-bonding allows us to observe the phenanthroline-catalyzed α-1,2-cis glycosylation is
scalar coupling using COSY experiment.[16] As shown illustrated in Figure 3. We hypothesize that the first
in Figure 2, scalar couplings (h3JHH) between the pyridine nitrogen atom of the phenanthroline catalyst
anomeric proton and Ha’ on the phenanthroline were C2 displaces the anomeric α-bromide leaving group of
observed for both intermediates Int1 and Int2. These glycosyl donor to form the β-phenanthrolinium ion
scalar interactions mediated by the lone pair electrons intermediate. This phenanthrolinium ion positions
on the second pyridine nitrogen of phenanthroline and equatorially to avoid the steric and electrostatic
the conjugated system are evidential for H-bonding interactions. Our recent DFT calculations suggest that
between the anomeric proton and the second nitrogen formation of the β-covalent phenanthrolinium ion
of phenanthroline. In order to obtain a clear view of intermediate is reversible.[10] The β-covalent glycosyl
1
4
the hydrogen bond coupling in H NMR, a rigid H- intermediate adopts the C1 chair conformation and is
bonding network is required.[19] As hydrogen bond in equilibrium with the α-glycosyl intermediate whose
formation is highly dependent on temperature,[20] we exists in the B2,5 boat conformation. Our NMR study
4
cooled the 1:1 mixture of glucosyl bromide 1* and C2 showed that these two key intermediates, a major C1
°
in CD2Cl2 to À 60 C and gradually warm to room β-phenanthrolinium ion conformer (Int1) and a minor
1
°
temperature. The H NMR spectra were taken at 10 C B2,5 α-phenanthrolinium ion conformer (Int2) were
1
interval and combined (Figure S3a). The H NMR formed in the reaction (Figure 2). To obtain high levels
°
spectrum was at highest resolution at À 10 C. The C1- of diastereoselectivity, a Curtin-Hammett situation
4
anomeric proton of Int1 (β) showed a defined allylic must be established: interconversion of the C1 chair-
°
splitting at À 10 C (see Figure S3b). Further, DFT like β-conformer and B2,5 boat-like α-conformer via an
optimized structures (Figure 2) for anomeric mixtures oxocarbenium ion intermediate is rapid and much
of the phenanthrolinium intermediates are consistent faster than the subsequent nucleophilic attack (Fig-
with the NMR observation: for Int1 (β) the H1À N’ ure 3). In the NMR study, these two intermediates
°
distance is 1.958 Å and the C1À H1À N angle is 133 , were formed and equilibrated within 30 min while the
°
while those for Int2 (α) are 2.089 Å and 117 .
product formation typically required more than 1 h to
Figure 3. Possible mechanism of phenanthroline-catalyzed glycosylation
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be observable. To rationalize the diastereoselectivity
for the major α-1,2-cis product, hydroxyl acceptor
4
preferentially approaches to the α-face of the C1 chair
conformation of the β-glycosyl phenanthrolinium ion
intermediate via an SN2 pathway. This would preclude
the reaction proceeding through a disfavored B2,5 boat
conformation of the α intermediate, which leads to the
minor β-1,2-trans product.
4
To further verify that the C1 chair-like β-glycosyl
phenanthrolinium is indeed the reactive intermediate,
we sought to detect the intermediates for 2-deoxy-2-
fluoro glycosyl bromide donor. The highly reactive
tribenzyl 2-fluoro galactosyl bromide 4 was chosen as
a model electrophile (Figure 4). The transient glycosyl
phenanthrolinium ion intermediate (Int3) was detected
1
by H NMR within several minutes (Figure 4) using a
1:1 mixture of 2-fluoro glycosyl bromide 4 and C2
°
catalyst at 25 C. Importantly, only the β-glycosyl
phenanthrolinium ion intermediate Int3 (Figure 3)
existing in the 4C1 chair conformation was observed. In
addition, more than 90% of 4 were converted to the
Int3 intermediate within 2 h. Unlike the tetrabenzyl
glycosyl bromide donor 1*, which produces highly
interconvertible intermediates (Int1 and Int2, Figure 2),
Scheme 3. Effect of the Configuration of Glycosyl Bromide
the 2-fluoro galactosyl bromide 4 generates a more anomerized to the corresponding a 2:1 α/β mixture in
stable intermediate (Int3), which results in either the absence of the phenanthroline catalyst. However, a
formation of the products or reverts to the reactant 4. 5:1 β/α mixture 5β/α converted exclusively to the
This observation was further supported by DFT corresponding α-isomer 5α in the presence of 15 mol%
°
calculations.[10]
of C1 catalyst (vide infra, Table 1) within 1 h at 25 C
The preferential formation of α-glucosides from α- (Scheme 3A). We also performed the reaction of a 5:1
glucosyl bromide in the presence of added bromide ion β/α mixture 5β/α with galactoside acceptor 2 under the
°
(Bu4NBr) was first described by Lemieux and attrib- influence of C1 catalyst at 25 C. We observed isomer-
uted to the enhanced reactivity of the higher energy β- ization of this 5:1 β/α mixture to α-isomer 5α is faster
glycosyl bromide.[21] As such, we evaluated if the than formation of the coupling product 6 at 25 C
°
stereochemistry of the α-1,2-cis product would be (Scheme 3B). On the other hand, coupling of 2 with
dictated by the configuration of glycosyl bromide at this 5:1 β/α mixture 5β/α under standard C1-catalyzed
the anomeric carbon.[8] Because it is difficult to obtain conditions provided 6 (Scheme 3C) in comparable
β-isomer of glycosyl bromide in a pure form, a 5:1 yield and α-selectivity to that obtained with α-isomer
mixture of β- and α-isomers of glycosyl bromide 5β/α 5α (Scheme 3D). Collectively, these results suggest
with β-isomer being a major diastereomer was used as that β-isomer of glycosyl bromide is not the reacting
a model substrate (Scheme 3).[8] We observed that a partner in the phenanthroline-catalyzed reaction. This
5:1 β/α mixture of starting material 5β/α slowly catalysis, which derives its α-stereoselectivity from the
highly reactive β-covalent phenanthrolinium ion inter-
mediate, is different from the Lemieux system.[21]
Double SN2 Mechanism? To further verify the
glycosylation reaction undergoes double SN2-like
mechanism, we conducted kinetic investigation. Based
on the NMR study, the rate of reaction is first order in
the concentration of glycosyl bromide, hydroxyl, and
catalyst. We reported the rate of phenanthroline C1-
catalyzed glycosylation of 2-propanol with 3,4,6-tri-
acetyl-2-O-benzyl-α-glucopyranosyl bromide 5α is
first-order in the concentration of alcohol and C1
catalyst. In addition, the saturation behavior in 2-
propanol concentration was observed.[8] However, due
Figure 4. Conformation of the 2-deoxy-2-fluoro glycosyl phe-
nanthrolinium ion and ROESY (blue) NMR evidence (see
supporting information for full spectrum).
to solubility issue, we were not able to conduct the
kinetic study with high concentration of glycosyl
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bromide 5α. In addition, we were not able to lower the glycosylation undergoes associative mechanisms
glycosyl bromide concentration as the experiment (likely double SN2).
required 60 h to obtain sufficient data under standard
C1-catalyzed conditions.
The rates of phenanthroline-catalyzed reactions
with different substituents on the phenanthroline
To verify the glycosylation reaction is first-order framework were also investigated. As illustrated in
dependent in the concentration of glycosyl bromide, Figure 6, all three phenanthroline catalysts provide
we adapted the reagent system used in the NMR study similar rate profile, where the overall rates are apparent
and conducted kinetic experiment at varying glycosyl zero-order kinetics in substrates and showing no
bromide concentration. The experiments were carried induction period. Due to the electron donating effect of
°
at 25 C in CD2Cl2 with glucosyl bromide 1* and 2 as the piperidine substituents, the rate of C2-catalyzed
the coupling partners, using C2 catalyst, DTBMP, and glycosylation should be faster than that of C1 and C3
mesitylene as internal standard. As illustrated in Fig- (vide infra, Table 1). As predicted, the C2-catalyzed
ure 5a, the product concentration appeared linear reaction is more rapid than both C1- and C3-catalyzed
relationship to time (apparent zero-order kinetics in reaction. On the other hand, both C1 and C3 showed
substrates), and induction period was not observed. In similar rate, complementary to the observation in
addition, the rate of product formation increases as the Table 1 (vide infra).
concentration of glucosyl bromide 1* increases. The
Influence of Phenanthroline To further validate
initial rate of reaction in Figure 5b showed first-order the reaction outcome with the kinetic study (Figure 6),
dependence on glycosyl bromide 1*. Unfortunately, we first conducted the coupling of nucleophile 2 with
due to limiting amount of donor 1*, we were not able undeuterated tetrabenzyl glucosyl bromide 1 in the
to observe the saturation behavior in glucosyl bromide presence of 15 mol% of C1, C2, and C3 (Table 1). To
concentration. However, the collective kinetic studies distinguish the reactivity of different catalysts, we kept
°
suggest that the phenanthroline catalyzed α-selective the reaction time for 5 h at 25 C. Use of C1 provided
disaccharide 3 in 40% yield with α:β=13:1 (entry 1).
In contrast, use of C2 provided 3 in higher high yield
(67%, entry 3). The non-substituted phenanthroline C3
yielded slightly less product compare to C2 (67% vs.
40%, entry 5 vs. 3). These results are complementary
to the kinetic experiment observed in Figure 6. As we
observed in the NMR study, the C2-symmetry of
phenanthroline plays critical role in the glycosylation.
As such, we evaluated the mono-piperidine substituted
phenanthroline C4, and a reduced yield of product 3
(24%, entry 7) was obtained in comparison to the
symmetrical catalyst C2 (entry 3), confirming the
critical role of the symmetry on phenanthroline. Benzo
[h]quinoline (C5, entry 8) catalyst is less reactive and
α-stereoselective, further validating the hydrogen bond
Figure 5. (a) Product concentration versus time for phenanthro-
line-catalyzed (C2, 0.02 M) glycosylation with varying glycosyl
bromide concentration: 0.2 M 1* (*, green), 0.4 M 1* (~, red)
and 0.6 M 1* (◆, blue). Reaction conditions: donor 1* (0.2–
0.6 M), acceptor 2 (0.2 M), C2 (0.02 M), DTBMP (0.4 M),
Figure 6. Product concentration versus time for the phenanthro-
line-catalyzed glycosylation with three different phenanthroline
catalysts: C1 (*, orange), C2 (~, red) and C3 (◆, dark blue).
Reaction condition: 1* (0.4 M), 2 (0.2 M), catalyst (0.02 M),
°
CD2Cl2 (5 mL), 25 C; (b) the initial rate of reaction is
°
dependent on the concentration of 1*.
DTBMP (0.4 M), CD2Cl2 (5 mL), 25 C.
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Table 1. Influence of Phenanthroline-Based Catalysts[a]
55% yield with moderate α-selectivity (α:β=7:1,
entry 1).[8] This result suggests that the SN1-SN2
reaction paradigm is slightly shifted in the presence of
the hindered alcohol 10. Use of DTBMP as acid
scavenger led slightly increase in yield (55%!71%)
and α-selectivity (7:1!10:1) in favor of 16. Use of C2
as the catalyst maintained the yield and selectivity
(entry 1). Although the α/β selectivity of the resulting
1
disaccharide 16 was determined by the standard H
NMR analysis, it can be challenging due to the overlap
of the anomeric protons with the benzyl protons. This
issue was overcome by introducing the 4-fluorobenzyl
group onto C6 of glucoside acceptor 11, wherein the α/
β selectivity of the resulting disaccharide 17 was
determined using 19F NMR (entry 2).[22] The ArF-
resonance of α-isomer 17 appeared at δF =
À 115.07 ppm while β-isomer counterpart appeared at
δF =À 114.49 ppm. Although coupling of 11 with
donor 1, under the influence of C1 result in slightly
higher yield compared to the C2, diastereoselectivity
significantly improved (10:1!20:1, entry 2) using C2
catalyst. Notably, when we coupled galactosyl bromide
7 to C4-hydroxyl 11 under the influence of both C1
and C2, the yield of the coupling product 18 increased
while α-selectivity remained excellent compared to
glucosyl bromide 1 (entry 3). Again, C2 catalyst is
more α-selective than C1 catalyst.
Next, we examined the glycosylation reaction of
challenging C4-hydroxyl rhamnose acceptor 12 with
L-fucosyl bromide 8 (Table 2, entry 4). Under the
influence of C1, the coupling product 19 (entry 4)
were obtained in moderate α-selectivity (α:β=5:1).
Diastereoselectivity of 19 significantly improved
(5:1!12:1) using C2. An important consequence of
C2 is its effectiveness with many different coupling
partners. For example, C1-catalyzed glycosylation of
[a] All reactions were conducted with 1 (0.2 mmol) and 2
(0.1 mmol) in MTBE (0.5 M).
[b] Yield of isolated 3 averaged over two to three runs.
[c] Diastereoselectivity (α:β) was determined by 1H NMR.
role of the second nitrogen atom on the phenanthroline serine residue 13 with 8 provided glycoconjugate 20
to the C1-hydrogen of the sugar moiety observed by with moderate α-selectivity (α:β=6:1, entry 5). In
NMR study (Figure 2). In our NMR study (Figures 1 contrast, use of C2 in the analogous reaction substan-
and 2), DTBMP was used as acid scavenger of HBr to tially increased in selectivity from 6:1 to 11:1 in favor
avoid the side-product previously observed with use of of α-1,2-cis glycoside 20. We also noted that C2
IBO.[10] Further exploration revealed that replacement catalyst is more selective with electron-withdrawing
of IBO with DTBMP as acid scavenger resulted in acceptor 15 (α:β=16:1, entry 7) than with electron-
improved α-1,2-cis diastereoselectivity while maintain- donating acceptor 14 (α:β=8:1, entry 6). We rational-
ing comparable yield (entries 2 and 4 vs 1 and 3). We ized that the less reactive nucleophile 15 allows the
rationalized that utilizing DTBMP as acid scavenger equilibrium of the reactive glycosyl intermediates
would preserve bromide ion in the reaction, which shifts toward β-glycosyl phenanthrolinium ion (Fig-
further facilitating the equilibrium between the glyco- ure 3), further enhancing the diastereoselectivity of the
syl phenanthrolinium ion intermediate and the α- final product 22. Unfortunately, the phenanthroline
glycosyl bromide (Figure 3).[10]
system proved to be less robust with the combination
Reaction Scope. Based on the results obtained in of highly unreactive donor 9 and highly hindered
Table 1 and with kinetic study, we next examined the acceptor 10 (entry 8).
ability of C2 catalyst with the highly hindered D-
Next, we sought to evaluate the performance of
glucose and L-rhamnose 4-hydroxyl acceptors 10–12 functionally complex nucleophiles in the site-selective
(Table 2) with electron-donating glycosyl bromide reaction catalyzed by C2 catalyst (Scheme 4).[23]
donors. For instance, coupling of 10 with a donor 1, Dexamethasone 24, bearing a variety of functional
under the influence of C1, provided disaccharide 16 in groups and three hydroxyls, is an anti-inflammatory
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Table 2. Stereoselective Glycosylation Reactions Using C1 and C2 Catalysts.[a]
[a] All reactions were conducted with glycosyl bromide (0.2 mmol) and alcohol acceptor (0.1 mmol) in MTBE (0.5 M).
[b] Reaction complete at 24 h.
[c] Reaction was allowed to stir for 48 h.
[d] Yield of isolated products averaged over two to three runs.
[e] The α/β selectivity was determined either by 1H NMR or by 19F NMR.
[f] Reaction was run in CH2Cl2.
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Scheme 4. C2-Catalyzed Site-Selective Couplings of Functionally Diverse Substrates.
and immunosuppressive corticosteroid that has been incorporated with an alkyl hydroxyl as well as an
used as the drug to treat severe COVID-19 patients.[24] unprotected C1-hemiacetal functionality. Ideally, the
Although there are three potential coupling sites in primary or secondary alkyl hydroxyl would be chemo-
dexamethasone 24, we hypothesized that a primary selectively glycosylated in the presence of the C1-
hydroxyl would be the preferred site. As expected, a hemiacetal. The resulting hemiacetal-terminated dis-
58% yield of the coupling product 25 was obtained accharide can be directly converted into a glycosyl
with high selectivity (α:β=10:1) and complete site- donor or is directly used as an electrophilic donor for
selectivity (Scheme 4A) when C2 was employed in the another coupling iteration to selectively furnish the
reaction. Estriol 26, bearing three hydroxyl groups at corresponding oligosaccharide. The key issue of
the C3, C16, and C17 positions, was then evaluated to chemoselectivity relies on the nucleophilic difference
furnish a 6:1 mixture of regioisomers 27 and 28 between the alkyl hydroxyls and the C1-hydroxyl
(Scheme 4B) in 60% yield with almost exclusive α- within the carbohydrate acceptor itself. Due to the
selectivity. In this reaction, the C16-hydroxyl is the inductive effect of the pyranose ring oxygen, we
preferred site for glycosylation forming 27 as a major hypothesized that an alkyl hydroxyl is likely to be
product while the more hindered C17-hydroxyl site more nucleophilic than a C1-hydroxyl. The influence
afforded minor product 28. More importantly, the of donor reactivity in chemoselective glycosylation
glycosylation at the C3-phenol site was not observed reactions has been well-documented.[25] In contrast, our
in the reaction, suggesting that that an alkyl hydroxyl chemoselective glycosylation strategy focuses on the
can be site-selectively coupled in the present of a effect of acceptor nucleophilicity, which has been
phenol nucleophile.
underdeveloped.[27]
Chemoselective Glycosylation. In typical ap-
We aimed to address these limitations by examining
proaches to the synthesis of oligosaccharides, an the efficacy of the C2 catalyst to promote both stereo-
electrophile is glycosylated with a nucleophile in the and chemoselective glycosylation of carbohydrate diol
presence of external reagents or catalysts, and the acceptors. Furthermore, the concept of chemoselectiv-
resulting disaccharide undergoes additional steps for ity can only be realized under the conditions that do
selective anomeric deprotection followed by installa- not promote oligomerization of the carbohydrate diol.
tion of an anomeric latent leaving group after each To validate the critical questions of stereo- and chemo-
coupling. In principles, C2-controlled approach could selectivity, a coupling of 1,6-diol acceptor 29 with
streamline the needs for anomeric deprotection and glycosyl bromide 1 was examined under the influence
protecting group manipulations. We envisioned that a of C2 (Table 3, entry 1).
glycosyl bromide is activated by C2 catalyst and
We selected diol 29 to test the feasibility of the
subsequently coupled to a carbohydrate acceptor chemoselective concept as it incorporates a relatively
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Table 3. C2-Catalyzed Chemoselective Glycosylation.[a]
entries 4). The diol 30 incorporates a highly hindered
C4-hydroxyl as the preferred site for the coupling to
take place. To our excitement, coupling of diol 30 with
electron-withdrawing glycosyl bromide 5α donor (en-
try 4) also proceeded with complete chemoselectivity
to afford the 1,4-linked disaccharide 34 in 70% yield
with high diastereoselectivity (α:β=11:1). More im-
portantly, self-coupling of 1,4-diol acceptor 30 to form
1,1-linked disaccharide was also not observed in the
reactions.
Orthogonal Glycosylation. The concept of orthog-
onal glycosylation focuses on the relative reactivities
of glycosyl donors, which can be modulated by
protecting groups and anomeric latent leaving group.
Successful glycosylations require the anomeric leaving
group of each carbohydrate coupling partner to be
chemically distinct and activated by different
reagents.[28] The orthogonal glycosylation strategy
streamlines the need for anomeric derivatization steps
as the coupling products are directly used as glycosyl
donors for subsequent glycosylation. This concept has
been applied to the synthesis of complex
oligosaccharides.[28] However, subtle changes to the
structures of carbohydrate coupling partners and
protecting groups could impact glycosylation selectiv-
ity and reactivity. In addition, the process is not
catalytic. We sought to assess the efficiency of C2
catalyst to promote the couplings of carbohydrate
coupling partners possessing chemically distinct
anomeric leaving groups. Thioglycoside 35 and glyco-
syl bromide 1 was used in the first combination
(Scheme 5A) as their anomeric leaving groups can be
activated by different sets of external reagent and
catalyst. The C2 catalyzed orthogonal reaction was
evaluated under optimized standard conditions with
use of dichloromethane as a solvent because thioglyco-
side 35 was partially soluble in MTBE. The disacchar-
ide product 36 (Scheme 5A) was obtained in 89% yield
with good α-selectivity (α:β=8:1). Similarly, the
[a] Reactions were conducted with glycosyl bromide (0.1 mmol)
and diol acceptor (0.15 mmol) in MTBE (0.5 M).
[b] Reactions were conducted with 0.3 mmol diol acceptor.
[c] Yield of isolated products averaged over two to three runs.
[d] The α/β selectivity was determined either by 1H NMR or by
19F NMR.
unhindered C6-hydroxyl as the preferred site for
glycosylation. Under optimal C2-catalyzed conditions,
the desired hemiacetal-terminated disaccharide 31 was
obtained in 63% yield with excellent stereoselectivity
(α:β=11:1) and complete chemoselectivity (entry 1).
Importantly, self-coupling of diol acceptor 29 to form
1,1’-linked disaccharide was not observed in the
reaction. We next examined fluorinated diol acceptor
29 in glycosylations with glycosyl bromide donors 4
and 8 (entries 2 and 3), the yields and α-selectivities of
these reactions were excellent (80%, α:β�20:1).
Notably, these glycosylation reactions proceeded with
complete chemoselectivity.
Having demonstrated that the C2-catalyzed chemo-
selective couplings of primary alcohols within carbo-
hydrate acceptors in the presence of free C1-hydroxyls,
this chemistry was further explored with secondary
alcohol within carbohydrate acceptor 30 (Table 3,
Scheme 5. C2-Catalyzed Orthogonal Glycosylations.
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combination of glycosyl fluoride 37 and glycosyl
bromide 1 under the influence of C2 catalyst provided
disaccharide 38 (Scheme 5B) in good yield and
selectivity.
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Conclusion
A systematic mechanistic investigation of the 4,7-
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4
adopts a C1 chair conformation while the α-isomer
adopts a B2,5 boat conformation. These two glycosyl
4
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1
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4
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operates by associative mechanisms.
Experimental Section
To a 10 mL oven-dried Schlenk flask, added alcohol 2
(0.1 mmol, 1.0 equiv.), catalyst (0.015 mmol, 15 mol%), acid
scavenger (IBO or DTBMP, 0.2 mmol, 2.0 equiv.), then trans-
ferred glycosyl bromide 1 (0.2 mmol, 2 equiv.) with MTBE
°
(0.2 mL). The resulting solution was stirred at 25 C for 5 h,
then directly subjected to Biotage Isolera One purification
system to give 3 as a colorless syrup.
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Acknowledgements
This research was supported by the National Institutes of Health
(R01GM098285). The authors would like to thank Prof.
Schlegel and Dr. Schaugaard at Wayne State University for
their helpful advice and assistance in DFT calculations. The
authors also would like to thank the Wayne State University
Chemistry Lumigen Center for instrument assistance.
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RESEARCH ARTICLE
A Mechanistic Probe into 1,2-cis Glycoside Formation
Catalyzed by Phenanthroline and Further Expansion of Scope
Adv. Synth. Catal. 2021, 363, 1–14
J. Li, H. M. Nguyen*